Huston Shaunna M, Ngamskulrungroj Popchai, Xiang Richard F, Ogbomo Henry, Stack Danuta, Li Shu Shun, Timm-McCann Martina, Kyei Stephen K, Oykhman Paul, Kwon-Chung Kyung J, Mody Christopher H
Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
Department of Microbiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
J Immunol. 2016 Feb 1;196(3):1259-71. doi: 10.4049/jimmunol.1501089. Epub 2016 Jan 6.
Cryptococcus gattii is an emerging fungal pathogen on the west coast of Canada and the United States that causes a potentially fatal infection in otherwise healthy individuals. In previous investigations of the mechanisms by which C. gattii might subvert cell-mediated immunity, we found that C. gattii failed to induce dendritic cell (DC) maturation, leading to defective T cell responses. However, the virulence factor and the mechanisms of evasion of DC maturation remain unknown. The cryptococcal polysaccharide capsule is a leading candidate because of its antiphagocytic properties. Consequently, we asked if the capsule of C. gattii was involved in evasion of DC maturation. We constructed an acapsular strain of C. gattii through CAP59 gene deletion by homologous integration. Encapsulated C. gattii failed to induce human monocyte-derived DC maturation and T cell proliferation, whereas the acapsular mutant induced both processes. Surprisingly, encapsulation impaired DC maturation independent of its effect on phagocytosis. Indeed, DC maturation required extracellular receptor signaling that was dependent on TNF-α and p38 MAPK, but not ERK activation, and the cryptococcal capsule blocked this extracellular recognition. Although the capsule impaired phagocytosis that led to pH-dependent serine-, threonine-, and cysteine-sensitive protease-dependent Ag processing, it was insufficient to impair T cell responses. In summary, C. gattii affects two independent processes, leading to DC maturation and Ag processing. The polysaccharide capsule masked extracellular detection and reduced phagocytosis that was required for DC maturation and Ag processing, respectively. However, the T cell response was fully restored by inducing DC maturation.
加氏隐球菌是加拿大和美国西海岸一种新出现的真菌病原体，可在原本健康的个体中引发潜在致命感染。在之前对加氏隐球菌可能颠覆细胞介导免疫机制的研究中，我们发现加氏隐球菌无法诱导树突状细胞（DC）成熟，导致T细胞反应存在缺陷。然而，其毒力因子以及逃避DC成熟的机制仍不清楚。由于其抗吞噬特性，隐球菌多糖荚膜是主要候选因素。因此，我们探究加氏隐球菌的荚膜是否参与逃避DC成熟。我们通过同源整合缺失CAP59基因构建了一株加氏隐球菌无荚膜菌株。有荚膜的加氏隐球菌无法诱导人单核细胞来源的DC成熟和T细胞增殖，而无荚膜突变体则能诱导这两个过程。令人惊讶的是，荚膜化损害DC成熟，与其对吞噬作用的影响无关。实际上，DC成熟需要依赖肿瘤坏死因子-α和p38丝裂原活化蛋白激酶（MAPK）而非细胞外信号调节激酶（ERK）激活的细胞外受体信号传导，而隐球菌荚膜阻断了这种细胞外识别。虽然荚膜损害吞噬作用，导致pH依赖的丝氨酸、苏氨酸和半胱氨酸敏感蛋白酶依赖的抗原加工，但不足以损害T细胞反应。总之，加氏隐球菌影响两个独立过程，导致DC成熟和抗原加工。多糖荚膜分别掩盖了细胞外检测并减少了DC成熟和抗原加工所需的吞噬作用。然而，通过诱导DC成熟，T细胞反应得以完全恢复。
